tbuckley/cabot-search huggingface dataset:
Topoisomerase 1 Inhibition in MYC-Driven Cancer Promotes Aberrant R-Loop Accumulation to Induce Synthetic Lethality
Authors: Peter Lin, Corey Lourenco, Jennifer Cruickshank, Luis Palomero, Jenna E. van Leeuwen, Amy H. Y. Tong, Katherine Chan, Samah El Ghamrasni, Miquel Angel Pujana, David W. Cescon, Jason Moffat, Linda Z. Penn
Journal: Cancer Research (2023)

Abstract MYC is a central regulator of gene transcription and is frequently dysregulated in human cancers. As targeting MYC directly is challenging, an alternative strategy is to identify specific proteins or processes required for MYC to function as a potent cancer driver that can be targeted to result in synthetic lethality. To identify potential targets in MYC-driven cancers, we performed a genome-wide CRISPR knockout screen using an isogenic pair of breast cancer cell lines in which MYC dysregulation is the switch from benign to transformed tumor growth. Proteins that regulate R-loops were identified as a potential class of synthetic lethal targets. Dysregulated MYC elevated global transcription and coincident R-loop accumulation. Topoisomerase 1 (TOP1), a regulator of R-loops by DNA topology, was validated to be a vulnerability in cells with high MYC activity. Genetic knockdown of TOP1 in MYC-transformed cells resulted in reduced colony formation compared with control cells, demonstrating synthetic lethality. Overexpression of RNaseH1, a riboendonuclease that specifically degrades R-loops, rescued the reduction in clonogenicity induced by TOP1 deficiency, demonstrating that this vulnerability is driven by aberrant R-loop accumulation. Genetic and pharmacologic TOP1 inhibition selectively reduced the fitness of MYC-transformed tumors in vivo. Finally, drug response to TOP1 inhibitors (i.e., topotecan) significantly correlated with MYC levels and activity across panels of breast cancer cell lines and patient-derived organoids. Together, these results highlight TOP1 as a promising target for MYC-driven cancers. Significance: CRISPR screening reveals topoisomerase 1 as an immediately actionable vulnerability in cancers harboring MYC as a driver oncoprotein that can be targeted with clinically approved inhibitors.
The Planning Fallacy in Patients With Chronic Lung Disease
Authors: Donald A. Redelmeier, Shina Namakian
Journal: JAMA Network Open (2023)

Joanna L. Hart, MD, MSHP; Amy E. Summer, MSW; Lon Ogunduyile, BA; Folasade C. Lapite, MBE; David Hong, BA; Casey Whitman, MS; Bryan S. Blette, PhD; Michael O. Harhay, PhD, MPH; Scott D. Halpern, MD, PhD
Prophylaxis Against <i>Pneumocystis</i> Pneumonia—Reply
Authors: Shiwei Zhou, Samuel L. Aitken
Journal: JAMA (2023)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Journals JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Medicare Physician Fee Schedule
Authors: Nicholas W. Rizer
Journal: JAMA (2023)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Journals JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2024 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Medicare Physician Fee Schedule
Authors: James C. Blankenship, Anita Arnold, Edward R. Tuohy
Journal: JAMA (2023)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Journals JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2024 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Medicare Physician Fee Schedule—Reply
Authors: Ezekiel J. Emanuel, Robert A. Berenson
Journal: JAMA (2023)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Journals JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2024 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Medicare Physician Fee Schedule
Authors: Christopher D. Jahraus, Paul E. Wallner, Dwight E. Heron
Journal: JAMA (2023)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Journals JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2024 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Galectin-3 aggravates microglial activation and tau transmission in tauopathy
Authors: Jian Jing Siew, Hui-Mei Chen, Feng-Lan Chiu, Chia-Wei Lee, Yao-Ming Chang, Hung-Lin Chen, Thi Ngoc Anh Nguyen, Hung-Ting Liao, Mengyu Liu, Hsiao-Tien Hagar, Yung-Chen Sun, Hsing-Lin Lai, Min-Hao Kuo, David Blum, Luc Buée, Lee-Way Jin, Shih-Yu Chen, Tai-Ming Ko, Jie-Rong Huang, Hung-Chih Kuo, Fu-Tong Liu, Yijuang Chern
Journal: Journal of Clinical Investigation (2023)

Alzheimer's disease is characterized by the accumulation of amyloid-β plaques, aggregation of hyperphosphorylated tau (pTau), and microglia activation. Galectin-3 (Gal3) is a β-galactoside-binding protein that has been implicated in amyloid pathology. Its role in tauopathy remains enigmatic. Here, we showed that Gal3 was upregulated in the microglia of humans and mice with tauopathy. pTau triggered the release of Gal3 from human induced pluripotent stem cell-derived microglia in both its free and extracellular vesicular-associated (EV-associated) forms. Both forms of Gal3 increased the accumulation of pathogenic tau in recipient cells. Binding of Gal3 to pTau greatly enhanced tau fibrillation. Besides Gal3, pTau was sorted into EVs for transmission. Moreover, pTau markedly enhanced the number of EVs released by iMGL in a Gal3-dependent manner, suggesting a role of Gal3 in biogenesis of EVs. Single-cell RNA-Seq analysis of the hippocampus of a mouse model of tauopathy (THY-Tau22) revealed a group of pathogenic tau-evoked, Gal3-associated microglia with altered cellular machineries implicated in neurodegeneration, including enhanced immune and inflammatory responses. Genetic removal of Gal3 in THY-Tau22 mice suppressed microglia activation, reduced the level of pTau and synaptic loss in neurons, and rescued memory impairment. Collectively, Gal3 is a potential therapeutic target for tauopathy.
Response to: Correspondence on ‘2023 ACR/EULAR antiphospholipid syndrome classification criteria’ by Tang<i>et al</i>
Authors: Medha Barbhaiya, Stephane Zuily, Alison M Hendry, Florian Manneville, Francis Guillemin, Karen H Costenbader, Doruk Erkan
Journal: Annals of the Rheumatic Diseases (2023)
Clinical status and future prospects of single-incision robotic-assisted surgery: a review
Authors: Xi Cheng, Chenhao Huang, Wenqing Jia, Zichao Guo, Yiqing Shi, Zijia Song, Haoran Feng, Haiyan Huang, Shuiyu Xu, Haosheng Li, Shaodong Wang, Yaqi Zhang, Tao Zhang, Kun Liu, Xiaopin Ji, Ren Zhao
Journal: International Journal of Surgery (2023)

Since the advent of conventional multiport laparoscopic surgery, the prosperity of minimally invasive surgery (MIS) has been thriving on the advancement of endoscopic techniques. Cosmetic superiority, recovery benefits and non-inferior surgical outcomes weigh single-incision laparoscopic surgery (SILS) as a promising modality. Although there are surgical challenges posed by steep learning curve and technological difficulties, such as instruments collision, triangulation loss and limited retraction, the establishment of robotic surgical platform as a solution to all is inspiring. Furthermore, with enhanced instrument maneuverability and stability, robotic ergonomic innovations adopt the advantages of SILS and surmount its recognized barriers by introducing a novel combination, single-incision robotic assisted surgery (SIRAS). As was gradually diffused in general surgery and other specialties, SIRAS manifests privileges in non-inferior clinical outcomes an satisfactory cosmetic effect among strictly-selected patients, and has the potential of a preferable surgical option for MIS.
Preferred Reporting Of Case Series in Surgery (PROCESS) 2023 guidelines
Authors: Ginimol Mathew, Catrin Sohrabi, Thomas Franchi, Maria Nicola, Ahmed Kerwan, Riaz Agha
Journal: International Journal of Surgery (2023)

Introduction: The PROCESS guidelines were developed in 2016 in order to improve the reporting quality of surgical case series. Since its inception, it has been updated twice, in 2018 and 2020, and has been cited over 1000 times. PROCESS guidelines have enjoyed great acceptance within the surgical research community. Our aim is to update the PROCESS guidelines in order to maintain its applicability in the field of surgical research. Methods: A PROCESS 2023 steering group was created. By working in collaboration, members of this group came up with proposals to update the PROCESS 2020 guidelines. These proposals were presented to an expert panel of researchers, who in turn scrutinised these proposals and decided whether they should become part of PROCESS 2023 guidelines or not, through a Delphi consensus exercise. Results: A total of 38 people participated in the development of PROCESS 2023 guidelines. The majority of items received a score between 7 and 9 from &gt;70% of the participants, indicating consensus with the proposed changes to those items. However, two items (3c and 6a) received a score between 7 and 9 from &lt;70% of the participants, indicating a lack of consensus with the proposed changes to those items. Those items will remain unchanged. Discussion: The updated PROCESS 2023 guidelines are presented with an aim to continue improving the reporting quality of case series in surgery.
Helen Salisbury: GPs and the fallout from patient research
Authors: Helen Salisbury
Journal: BMJ (2023)

Helen Salisbury: GPs and the fallout from patient research Helen Salisbury GP GPs spend a lot of time talking to patients about test results, and this can be difficult if those tests were performed outside the NHS.Some people choose to undergo tests offered by commercial companies-often as part of a "wellness check"-or they may accept invitations to participate in research projects.In either case, if abnormalities are found they turn to their GP.
Euglycemic Ketoacidosis in Two Patients Without Diabetes After Introduction of Sodium–Glucose Cotransporter 2 Inhibitor for Heart Failure With Reduced Ejection Fraction
Authors: Mahesh M. Umapathysivam, James Gunton, Steve N. Stranks, David Jesudason
Journal: Diabetes Care (2023)

OBJECTIVE Ketoacidosis induced by sodium–glucose cotransporter 2 inhibitor (SGLT2i) treatment has been consistently observed in clinical practice in patients with type 2 diabetes despite minimal indication from the landmark cardiovascular outcome trials. It has been postulated that individuals without diabetes will not develop this complication due to an adequate insulin secretory capacity, which will protect against significant ketone formation. Cardiovascular outcome trials examining SGLT2i use in individuals with heart failure but not diabetes have not reported ketoacidosis. RESEARCH DESIGN AND METHODS We describe the first two case reports of severe nondiabetic ketoacidosis after initiation of an SGLT2i for the treatment of heart failure with reduced ejection fraction, and we describe the management strategies employed and implication for the pathophysiology of SGLT2i-associated ketoacidosis. RESULTS Each individual presented with ketoacidosis triggered by reduced oral nutrition intake. For both individuals, ketoacidosis resolved with intravenous glucose administration, encouragement of consumption of oral glucose-containing fluid, and minimal insulin administration. CONCLUSIONS These two cases demonstrate that SGLT2i-associated ketoacidosis is possible in individuals without diabetes.
Revisiting Aurora Kinase B: A promising therapeutic target for cancer therapy
Authors: Naga Rajiv Lakkaniga, Zhengyu Wang, Yao Xiao, Anupreet Kharbanda, Li Lan, Hong‐yu Li
Journal: Medicinal Research Reviews (2023)

Abstract Cancer continues to be a major health concern globally, although the advent of targeted therapy has revolutionized treatment options. Aurora Kinase B is a serine‐threonine kinase that has been explored as an oncology therapeutic target for more than two decades. Aurora Kinase B inhibitors show promising biological results in in‐vitro and in‐vivo experiments. However, there are no inhibitors approved yet for clinical use, primarily because of the side effects associated with Aurora B inhibitors. Several studies demonstrate that Aurora B inhibitors show excellent synergy with various chemotherapeutic agents, radiation therapy, and targeted therapies. This makes it an excellent choice as an adjuvant therapy to first‐line therapies, which greatly improves the therapeutic window and side effect profile. Recent studies indicate the role of Aurora B in some deadly cancers with limited therapeutic options, like triple‐negative breast cancer and glioblastoma. Herein, we review the latest developments in Aurora Kinase B targeted research, with emphasis on its potential as an adjuvant therapy and its role in some of the most difficult‐to‐treat cancers.
Attenuating Epithelial‐to‐Mesenchymal Transition in Cancer through Angiopoietin‐Like 4 Inhibition in a 3D Tumor Microenvironment Model
Authors: Zehuan Liao, Joseph Jing Heng Lim, Jeannie Xue Ting Lee, Damien Chua, Marcus Ivan Gerard Vos, Yun Sheng Yip, Choon Boon Too, Huan Cao, Jun Kit Wang, Yufeng Shou, Andy Tay, Kaisa Lehti, Hong Sheng Cheng, Chor Yong Tay, Nguan Soon Tan
Journal: Advanced Healthcare Materials (2023)

Epithelial-to-mesenchymal transition (EMT) plays a crucial role in metastatic cancer progression, and current research, which relies heavily on 2D monolayer cultures, falls short in recapitulating the complexity of a 3D tumor microenvironment. To address this limitation, a transcriptomic meta-analysis is conducted on diverse cancer types undergoing EMT in 2D and 3D cultures. It is found that mechanotransduction is elevated in 3D cultures and is further intensified during EMT, but not during 2D EMT. This analysis reveals a distinct 3D EMT gene signature, characterized by extracellular matrix remodeling coordinated by angiopoietin-like 4 (Angptl4) along with other canonical EMT regulators. Utilizing hydrogel-based 3D matrices with adjustable mechanical forces, 3D cancer cultures are established at varying physiological stiffness levels. A YAP:EGR-1 mediated up-regulation of Angptl4 expression is observed, accompanied by an upregulation of mesenchymal markers, at higher stiffness during cancer EMT. Suppression of Angptl4 using antisense oligonucleotides or anti-cAngptl4 antibodies leads to a dose-dependent abolishment of EMT-mediated chemoresistance and tumor self-organization in 3D, ultimately resulting in diminished metastatic potential and stunted growth of tumor xenografts. This unique programmable 3D cancer cultures simulate stiffness levels in the tumor microenvironment and unveil Angptl4 as a promising therapeutic target to inhibit EMT and impede cancer progression.
Management of locally advanced non‐small cell lung cancer: State of the art and future directions
Authors: Da Miao, Jing Zhao, Ying Han, Jiaqi Zhou, Xiuzhen Li, Ting Zhang, Wen Li, Yang Xia
Journal: Cancer Communications (2023)

Abstract Lung cancer is the second most common and the deadliest type of cancer worldwide. Clinically, non‐small cell lung cancer (NSCLC) is the most common pathological type of lung cancer; approximately one‐third of affected patients have locally advanced NSCLC (LA‐NSCLC, stage III NSCLC) at diagnosis. Because of its heterogeneity, LA‐NSCLC often requires multidisciplinary assessment. Moreover, the prognosis of affected patients is much below satisfaction, and the efficacy of traditional therapeutic strategies has reached a plateau. With the emergence of targeted therapies and immunotherapies, as well as the continuous development of novel radiotherapies, we have entered an era of novel treatment paradigm for LA‐NSCLC. Here, we reviewed the landscape of relevant therapeutic modalities, including adjuvant, neoadjuvant, and perioperative targeted and immune strategies in patients with resectable LA‐NSCLC with/without oncogenic alterations; as well as novel combinations of chemoradiation and immunotherapy/targeted therapy in unresectable LA‐NSCLC. We addressed the unresolved challenges that remain in the field, and examined future directions to optimize clinical management and increase the cure rate of LA‐NSCLC.
Hot topics in allergen immunotherapy, 2023: Current status and future perspective
Authors: Magdalena Zemelka‐Wiacek, Ioana Agache, Cezmi A. Akdis, Mübeccel Akdis, Thomas B. Casale, Stephanie Dramburg, Karina Jahnz‐Różyk, Anna Kosowska, Paolo M. Matricardi, Oliver Pfaar, Mohamed H. Shamji, Marek Jutel
Journal: Allergy (2023)

The importance of allergen immunotherapy (AIT) is multifaceted, encompassing both clinical and quality-of-life improvements and cost-effectiveness in the long term. Key mechanisms of allergen tolerance induced by AIT include changes in memory type allergen-specific T- and B-cell responses towards a regulatory phenotype with decreased Type 2 responses, suppression of allergen-specific IgE and increased IgG
A Conserved Ribosomal Protein Has Entirely Dissimilar Structures in Different Organisms
Authors: Léon Schierholz, Charlotte R Brown, Karla Helena-Bueno, Vladimir N Uversky, Robert P Hirt, Jonas Barandun, Sergey V Melnikov
Journal: Molecular Biology and Evolution (2023)

Ribosomes from different species can markedly differ in their composition by including dozens of ribosomal proteins that are unique to specific lineages but absent in others. However, it remains unknown how ribosomes acquire new proteins throughout evolution. Here, to help answer this question, we describe the evolution of the ribosomal protein msL1/msL2 that was recently found in ribosomes from the parasitic microorganism clade, microsporidia. We show that this protein has a conserved location in the ribosome but entirely dissimilar structures in different organisms: in each of the analyzed species, msL1/msL2 exhibits an altered secondary structure, an inverted orientation of the N-termini and C-termini on the ribosomal binding surface, and a completely transformed 3D fold. We then show that this fold switching is likely caused by changes in the ribosomal msL1/msL2-binding site, specifically, by variations in rRNA. These observations allow us to infer an evolutionary scenario in which a small, positively charged, de novo-born unfolded protein was first captured by rRNA to become part of the ribosome and subsequently underwent complete fold switching to optimize its binding to its evolving ribosomal binding site. Overall, our work provides a striking example of how a protein can switch its fold in the context of a complex biological assembly, while retaining its specificity for its molecular partner. This finding will help us better understand the origin and evolution of new protein components of complex molecular assemblies-thereby enhancing our ability to engineer biological molecules, identify protein homologs, and peer into the history of life on Earth.